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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Enhanced Melanoma-Targeted Therapy by "Fru-Blocked" Phenyboronic Acid-Modified Multiphase Antimetastatic Micellar
Yang Long1, Zhengze Lu1, Ling Mei1
1Key Laboratory of Drug Targeting and Drug Delivery Systems West China School of Pharmacy Sichuan University No. 17, Block 3, Southern Renmin Road Chengdu 610041 China.
Abstract:
Metastasis remains the main driver of mortality in patients suffering from cancer because of the refractoriness resulting from the multi-phase metastatic cascade. Herein, a multifunctional self-delivering PBA-LMWH-TOS nanoparticle (PLT NP) is established that acts as both nanocarrier and anti-metastatic agent with effects on most hematogenous metastases of cancers. The hydrophilic segment (low molecular weight heparin, LMWH) inhibits the interactions between tumor cells and platelets. The hydrophobic segment (d-α-tocopheryl succinate, TOS) could inhibit the expression of matrix metalloproteinase-9 (MMP-9) in B16F10 cells which is first reported in this article. Surprisingly, even the blank NPs showed excellent anti-metastatic capacity in three mouse models by acting on different phases of the metastatic cascade. Moreover, the overexpression of sialic acid (SA) residues on tumor cells is implicated in the malignant and metastatic phenotypes of cancers. Thus, these 3-aminophenylboronic acid (PBA)-modified doxorubicin (DOX)-loaded NPs offer an efficient approach for the treatment of both solid melanomas and metastases. Furthermore, a simple pH-sensitive "Fructose (Fru)-blocking" coping strategy is established to reduce the NP distribution in normal tissues and distinctly increases the accumulation in melanoma tumors. These micellar NPs consisting of biocompatible materials offer a promising approach for the clinical therapy of highly invasive solid tumors and metastases.
Insights
A novel nanoparticle effectively targets cancer metastasis by inhibiting tumor cell-platelet interactions and matrix metalloproteinase-9. This approach shows promise for treating invasive solid tumors and metastases.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Metastasis is a primary cause of cancer mortality due to the complex metastatic cascade.
- Overexpression of sialic acid (SA) on tumor cells is linked to malignancy and metastasis.
- Existing treatments often struggle with the refractoriness of metastatic disease.
Purpose of the Study:
- To develop a multifunctional nanoparticle (PBA-LMWH-TOS) as both a nanocarrier and anti-metastatic agent.
- To investigate the anti-metastatic effects of the nanoparticle on various phases of the metastatic cascade.
- To establish a pH-sensitive targeting strategy for enhanced tumor accumulation.
Main Methods:
- Fabrication of self-delivering PBA-LMWH-TOS nanoparticles (PLT NPs).
- Evaluation of anti-metastatic effects in three mouse models.
- Investigation of mechanisms including inhibition of tumor cell-platelet interactions and MMP-9 expression.
- Development of a pH-sensitive "Fructose (Fru)-blocking" strategy for targeted delivery.
Main Results:
- PLT NPs demonstrated significant anti-metastatic capacity in mouse models.
- The hydrophilic LMWH segment inhibited tumor cell-platelet interactions.
- The hydrophobic TOS segment inhibited MMP-9 expression in B16F10 cells.
- Blank NPs exhibited notable anti-metastatic effects.
- The Fru-blocking strategy enhanced NP accumulation in melanoma tumors.
Conclusions:
- Multifunctional PLT NPs offer a promising strategy against hematogenous metastases.
- The developed NPs target multiple phases of the metastatic cascade.
- The pH-sensitive targeting strategy improves therapeutic efficacy for solid tumors and metastases.
- These biocompatible micellar NPs represent a potential clinical therapy for invasive cancers.
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